Continuing Education Activity
Progestins, or progestogens, are a class of synthetic hormone drugs that mimic progesterone's endogenous hormone. These drugs each act on the progesterone receptor. However, they have their own specific effects and are grouped based on generational class or their structural derivation. Progestins are used as medications in the management of a variety of conditions, including contraception and postmenopausal hormone replacement therapy (HRT), among others. This article reviews the mechanism of action, indications, contraindications, adverse events, and other key elements of progestin therapy in the clinical setting to benefit the members of a healthcare team managing the care of patients for which progestin may be of benefit.
- Describe the indications of progestins.
- Outline the contraindications of progestins.
- Explain the adverse effects of progestins.
A progestogen (also called progestagen, gestagen, or gestogen) is a molecule, either natural or synthetic, that shows similar effects as progesterone, binds to the progesterone receptor, and acts as an agonist. Progestins are synthetic progestogens. Progestin drugs can be subclassified in two ways: (1) generationally or (2) based upon structural properties. The generational subclassification is based upon when the group of progestins was introduced into the market, regardless of structure derivation, and consists of the first, second, third, and fourth generation. Fourth-generation progestins are newer preparations and have some antiandrogenic properties. Of particular importance is drospirenone, a fourth-generation progestin structurally related to spironolactone. When divided based upon structural properties, there are three major groupings to consider. These include pregnanes, estranes, and gonanes. Pregnanes are derived from progesterone, and the latter two are derived from testosterone. Estranes have more androgenic activity than gonanes. The testosterone derivatives are the majority of progestins used in contraceptives. Each of the progestin drugs is listed by their group below:
- Pregnanes: medroxyprogesterone acetate, nomegestrol acetate
- Estranes: Norethindrone, norethindrone acetate, ethynodiol diacetate, norethynodrel
- Gonanes: levonorgestrel, desogestrel, norgestimate, gestodene
Progestins are used in medications primarily for contraception, either alone or in combination with estrogen, and postmenopausal hormone replacement therapy (HRT), but they are also used in the treatment and management of a variety of other conditions. Contraceptive vaginal ring and transdermal patch contain estrogen and progestin combination. There are no differences in contraceptive efficacy among various progestins in combined oral contraceptives (COC: combined estrogen and progestin oral contraceptive pill). In women who use COC, there is a decrease in the risk of endometrial and ovarian cancer. Depot medroxyprogesterone acetate use also has been shown to reduce endometrial and ovarian cancer. There is a paucity of data with the progestin-only pill, progestin containing implants, and intrauterine devices.
Progestins are used with estrogens for contraceptive purposes:
- Combined oral contraceptives
- Contraceptive vaginal ring
- Transdermal patch
Progestins are also used without combination for contraceptive purposes:
- Progestin-only oral contraceptive pill: Norethindrone 0.35 mg tablets in the US, desogestrel 75 µg in Europe
- Depot medroxyprogesterone acetate (DMPA) injections
- Etonogestrel subcutaneous implant
- Levonorgestrel intrauterine device
- Postcoital contraception: levonorgestrel
The other postcoital contraceptive options do not involve progestins, ulipristal acetate, a progesterone receptor antagonist or modulator, and a copper T 380A intrauterine device.
Progestins, by themselves or in combination contraceptives, can be used to treat dysmenorrhea, irregular menstruation, abnormal uterine bleeding, and endometriosis-related pain. They are also indicated in the diagnostic evaluation of secondary amenorrhea. They are used in an emergency or postcoital (morning-after pill) contraception. Progestin-only contraceptives appear to be appropriate choices for many women with contraindications to estrogen-containing contraceptives or women who prefer to avoid estrogen exposure. Levonorgestrel is used in levonorgestrel-releasing intrauterine devices.
When used in combination with estrogen, progestin-containing contraceptives can be used to treat menstrual cycle disorders such as oligomenorrhea due to polycystic ovary syndrome, menstrual migraines, and premenstrual syndrome or premenstrual dysphoric disorder. They also can be used to suppress the formation of ovarian cysts. Progestins with less androgenic activity (mainly Gonanes) in combination with estrogen are indicated in the treatment hyperandrogenism (acne and hirsutism) from polycystic ovary syndrome and nonclassical congenital adrenal hyperplasia due to 21-hydroxylase deficiency.
Progestins, along with estrogen, can be used for hormone replacement in women with premature ovarian failure, menopause, and secondary (pituitary) or tertiary (hypothalamic) hypogonadism. Progestins are given with estrogens to postmenopausal women with an intact uterus for hormone replacement therapy. Estrogens can be administered orally, transdermally, or vaginally for hormone replacement therapy. Progestogens can be given as a continuous or cyclical regimen. In a cyclical regimen, women will have menstrual bleeding, an estrogen most commonly conjugated estrogens are given orally for 25 days, medroxyprogesterone acetate orally is given in the last 12 to 14 days of the estrogen administration. For 5-6 days, no hormone is given, and withdrawal bleeding is expected to occur. Continuous administration does not trigger a withdrawal bleeding, but intermittent spotting or bleeding can be seen, especially in the first year. Other postmenopausal hormone replacement therapy options include ethinyl estradiol and norethindrone acetate, estradiol and norethindrone, estradiol and norgestimate, and estradiol and drospirenone combinations.
Estrogens and progestins are used to stimulate puberty and secondary sexual characteristics in women with primary ovarian failure, for example, Turner syndrome.
Progesterone therapy has been used to prevent preterm labor. Progesterone inhibits proinflammatory cytokines and delay cervical ripening and has been recommended to women who suffered a previous preterm delivery and is at risk for it. Progesterone therapy has been shown to be effective in preventing miscarriage in women with both first-trimester vaginal bleeding and a history of more than 2 miscarriages.
Progesterone as micronized progesterone, progesterone in oil intramuscular injection, or vaginal micronized progesterone is used in in-vitro fertilization (IVF) protocols after placement of embryo(s) to uterus 3-5 days post-fertilization. GnRH agonists or antagonists are given before IVF suppress pituitary LH, which in turn cannot stimulate the corpus luteum. Progesterone is administered to support the embryo until the placenta takes over.
Progestins have a role in gender transition treatment in female- to- male transition. These women are treated with androgen. Androgens suppress ovarian sex steroid production by suppressing the pituitary, but if the suppression is not enough and the patient experiences breakthrough bleeding, depot medroxyprogesterone acetate 150 mg every 3 months can be given to prevent uterine bleeding.
Mechanism of Action
Progesterone enters the cell by passive diffusion through the plasma membrane and binds to the progesterone receptor in the nucleus. When unbound, the progesterone receptor exists as a monomer. After binding progesterone, the receptor undergoes a conformational change and becomes a dimer, which increases receptor binding to DNA. Most progestins exert their contraceptive effects by suppressing the secretion of gonadotropin-releasing hormone (GnRH) by the hypothalamus and luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by the pituitary gland. This adventitiously alters the menstrual cycle to suppress ovulation. Norethindrone can be somewhat of an exception, as half of the women taking it still ovulate. Progestins also provide other benefits by secondary mechanisms such as thickening cervical mucus to prevent penetration by sperm, slowing tubal motility by impairing fallopian tube motility, and inducing endometrial atrophy.
Progestin drugs are administered in a myriad of ways, and the choice is dependent on a variety of factors including, but not limited to, clinical indication, special populations, patient preferences, patient adherence, insurance coverage, and financial burden. The most commonly prescribed progestin-containing drugs are combination oral contraceptives (COCs). Other options for combination contraceptives consist of a transdermal patch and vaginal ring. However, women who desire a progestin-only contraceptive must decide among the norethindrone or drospirenone progestin-only pills (POPs), etonogestrel implant, levonorgestrel-releasing intrauterine devices (IUDs), and depot medroxyprogesterone acetate (DMPA) injection.
DMPA injections are given every three months and are available as 150 mg in 1 mL for intramuscular injection and 104 mg in 0.65 mL for subcutaneous injection. For progestin-only methods, the IUD and implant are the most effective options, followed by DPMA injections and then the pill. The progestin-only IUD, implant, and injectable are also more effective than combined oral contraceptives. An oral formulation of levonorgestrel is offered and sold over the counter as an emergency (postcoital) contraceptive or “morning-after pill.”
Neither combined oral contraceptives nor progestin-only contraceptives seem to cause weight gain (except for DPMA), but it is commonly reported by patients as a side effect. Furthermore, studies relating these contraceptives to possible impacts on mood and sexual function are limited and conflicting.
Combined Estrogen-progestin Contraception
Common complaints from a combined oral contraceptive include mild symptoms such as breast tenderness, nausea, headaches, bloating, and unscheduled bleeding, but these typically resolve in most of the users. Other side effects include increased risk of venous and arterial thromboembolism (DVT, PE, MI, stroke), mild increase in blood pressure, and possible increases in the risk of breast and cervical cancer. COCs also have been demonstrated to cause seemingly unfavorable changes in lipid and carbohydrate metabolism (increased triglycerides, decreased HDL and increased LDL cholesterol, increased insulin and glucose levels, and reduced insulin sensitivity). However, these changes are essentially negligible, unless patients belong to certain subgroups such as those with polycystic ovary syndrome. Furthermore, they typically pertain to older formulations with higher estradiol levels.
Unscheduled bleeding and changes in menses are the most common side effects associated with POPs, as they are the most well-tolerated of the progestin-only options. Other side effects include acne, hirsutism, and an increased prevalence of follicular ovarian cysts. Patients at risk for hyperkalemia, either by a medical condition (i.e., adrenal insufficiency) or medication (i.e., angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, potassium-sparing diuretics), should use drospirenone with caution due to its anti-mineralocorticoid activity similar to spironolactone.
The DMPA injection can delay returning to fertility for as long as 18 months after it is stopped and should not be chosen by women who are thinking about pregnancy within the next two years. According to the US Boxed Warning for DPMA from Lexicomp, it is not recommended for long-term use (>2 years) as a birth control method or as medical therapy for endometriosis-associated pain unless other options are considered inadequate. It also includes the following claims not indirectly addressed previously: (1) prolonged use of DPMA may result in a loss of bone mineral density and (2) the incidence of probable dementia was increased in women ≥65 years old taking conjugated estrogen in combination with DMPA.
Women who have undergone bariatric surgery and those taking certain medications that induce hepatic enzymes such as antibiotics (rifampin), antifungals (griseofulvin), and anticonvulsants (phenytoin, carbamazepine, topiramate, and barbiturates) are not advised to use combined or progestin-only contraception.
Combined Estrogen-progestin Contraception
Any factors that increase the risk of cardiovascular disease or thromboembolism are contraindications to COCs, due to the procoagulant effects of estrogen, and are considered an “unacceptable risk” as indicated with a Category 4 label. Category 4 denotes unacceptable health risk if the contraceptive is administered to subjects with the existing condition, basically a contraindication. These categories from 1 to 4 are outlined in detail by the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC). These include women ≥35 years old who smoke, two or more risk factors for cardiovascular disease (older age, smoking, diabetes, and hypertension), hypertension (≥160/≥100 mmHg), venous thromboembolism (unless on anticoagulation), thrombogenic mutations, ischemic heart disease, history of stroke, complicated valvular heart disease (pulmonary hypertension, risk of atrial fibrillation, history of subacute bacterial endocarditis), diabetes mellitus for longer than 20 years or diabetes with nephropathy, retinopathy, or neuropathy.
Other Category 4 contraindications: current breast cancer, cirrhosis, hepatocellular adenoma or malignant hepatoma, and migraine with aura.
It is recommended that postpartum women refrain from taking COCs for at least the first 21 days after delivery due to the procoagulant effect of pregnancy and the increased risk for VTE during this period. If breastfeeding, women should not take COCs until 30 days after delivery due to possible effects on lactation.
Most women with medical comorbidities are candidates for POPs. Contraindications to all progestin-only contraception types include many similarities to those of COCs: known or suspected pregnancy, known or suspected breast cancer, undiagnosed abnormal uterine bleeding, and benign or malignant liver tumors, severe cirrhosis, or acute liver disease. There are also contraindications specific to each progestin-only contraception as listed in Lexicomp and can be found below:
DPMA - hypersensitivity to medroxyprogesterone or any component of the formulation, active thrombophlebitis, thromboembolic disorders or cerebral vascular disease, estrogen or progesterone-dependent tumor
Etonogestrel - hypersensitivity to etonogestrel or any component of the formulation
Levonorgestrel - hypersensitivity to levonorgestrel or any component of the formulation, postcoital contraception, congenital or acquired uterine anomaly (distort the uterine cavity and would affect correct IUD placement), acute pelvic inflammatory disease, or history of pelvic inflammatory disease (unless there has been a subsequent intrauterine pregnancy), postpartum endometritis or infected abortion within past three months, known or suspected uterine or cervical malignancy, untreated acute cervicitis or vaginitis (including bacterial vaginosis) or other lower genital tract infections until the infection is controlled, conditions which increase susceptibility to pelvic infections.
Synthetic progestins have much longer half-lives (several hours) than endogenous progesterone (5-7 minutes). Metabolism of progestins occurs primarily by cytochrome P450 enzymes in the liver and excretion is via the urine. In general, there are no examinations or tests needed before initiation of contraception. The exceptions include blood pressure measurement if prescribing combined hormonal contraception and bimanual examination plus cervical inspection for IUDs. Women who have a current STI or those with a high likelihood of STI exposure should not undergo IUD insertion. Weight and BMI measurements are not needed for any contraceptive method but are recommended to establish a baseline. Any additional testing is not needed in most women (i.e. medically uncomplicated). Routine follow-up appointments specifically for contraception are also unnecessary.
All contraceptive methods can be started at any time during the cycle if reasonably certain the woman is not pregnant. If not started on the first day of menses, backup contraception (i.e. condom, abstinence) may be indicated. A common and often recommended approach with COCs is the “quick start” method, which is aimed to improve continuation rates and efficacy. In this method, the woman begins taking the pill on the day it is prescribed and then uses backup contraception for an additional seven days. This is necessary because the pill is often started >5 days after the onset of menses. However, initiation should be individualized for each patient so that it aligns with their preferences and priorities. The etonogestrel implant follows the same rules as COCs. If POPs are not started within the first five days, back-up contraception is needed for only two additional days due to the rapid effect on cervical mucus. In regard to the levonorgestrel IUD and DMPA injection, if they are started >7 days after the onset of menses, patients should use backup contraception for seven days.
The user failure rate with COCs is estimated to be 7%, and this rate with POPs is >7%. Missed pills are often the cause of contraceptive failure. This is especially of concern with POPs due to their short half-lives. It is also essential that they are taken at the same time each day. Norethindrone, in particular, must not be missed by more than 3 hours or the patient will be advised to use back-up contraception for two days. Missing a single pill on COCs is not as serious, as it does not reverse ovarian suppression, thus no further contraception is required. If a patient misses two or more COC pills, backup contraception should be used for seven days.
Although the reason for the user failure rate is multifactorial, it also important to consider certain populations when advising patients on the best choice of contraception. For example, oral contraceptives can be challenging for adolescents due to daily adherence and having to refill the prescription every month. The long-acting reversible methods (IUDs and implants) are considered first-line options for these patients by the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists.
Enhancing Healthcare Team Outcomes
Contraceptive selection is an equally complex and important decision. The goals of the healthcare team should be aimed toward providing high-quality, patient-centered counseling. Family planning care has evolved from a clinician directed approach aimed at preventing unwanted pregnancies to one of shared decision making eliciting patient preferences and reasons for seeking contraception. Furthermore, the shared decision-making approach provides the opportunity for preconception counseling and assessment for medical comorbidities that could affect the safety of certain methods. It serves as an encompassing model fit for all people for which contraception may be of benefit and protects against any bias. This has shown to increase patient knowledge, promote confidence in their choice, and improve overall patient satisfaction. The patients' ability to make informed decisions consistent with their values should be of utmost importance.